Ovarian cancer is one of the most common types of cancer, with a prevalence of 13.1 per 100,000 women in the United States and a death rate of 8.8 per 100,000 women. (Horner, et al. (eds.) SEER Cancer Statistics Review (1975-2006)). Ovarian cancer is relatively asymptomatic at its early stages with rare cases of incidental early diagnosis due to other diseases or symptoms. In about three-quarters of all cases of ovarian cancer, the patients present with peritoneal metastasis at the time of diagnosis. (Colombo, et al., Gynecol. Oncol. 122, 632-640 (2011)).
The standard primary treatment for advanced ovarian cancer includes cytoreduction surgery where the bulk of the tumor is removed via minimally invasive laparoscopic surgery, followed by intravenous (IV) or intraperitoneal (IP) chemotherapy with a platinum-based agent such as cisplatin.
The IP regimen requires surgeons to implant a catheter connected to a port (such as the BardPort®) during the cytoreduction surgery. Specifically, following the debulking of large visible tumors, two 5 mm incisions are made at the upper right and lower right quadrants of the abdomen. The port is inserted through the incision at the upper right quadrant and sutured subcutaneously. The tip of the catheter is tunneled subcutaneously to the incision in the lower right quadrant of the abdomen where it will enter the peritoneal cavity. Once every three weeks, the patient receives an infusion of 2 liters of cisplatin solution through the port and into the peritoneal cavity.
Although clinical trials have shown that the IP chemotherapy prolongs survival, many patients drop out of treatment due to catheter-related complications. (Armstrong, et al., N. Engl. J. Med. 354, 34-43 (2006)). For example, the implantation sites are prone to infection and inflammation over the period of treatment and the long catheter is susceptible to obstruction.
Pharmacokinetic studies have shown that the peak concentration of cisplatin in the peritoneal cavity reaches a level 20 times that in the systemic compartment, and the total area-under-curve concentration of cisplatin is 12 times that of systemic circulation if cisplatin is administered directly into the peritoneal cavity. (Markman, The Lancet Oncology 4, 277-283 (2003); Casper, et al., Cancer Treatment Reports 67, 235-238 (1983)). The Gynecology Oncology Group has conducted large phase III trials, comparing three different IV cisplatin treatment regimens to IP cisplatin treatment and found the latter to be able to prolong overall survival from 49.7 months in IV treatment to 65.6 months (p=0.03). (Armstrong, et al., N. Engl. J. Med. 354, 34-43 (2006)). However, 83% of subjects completed all cycles of IV therapy, but only 42% of subjects completed all cycles of IP therapy. The primary reason for dropping-out of IP treatment is catheter-related complications.
Furthermore, many medical practitioners hesitate to recommend the IP treatment modality due to the lack of familiarity among clinicians with peritoneal administration and catheter-placement techniques. This complex procedure currently can only be performed at premier cancer centers by trained personnel. Accordingly, there is a need for an alternative to IP administration that eliminates catheter-related complications to allow more patients to enjoy the benefits of IP therapy.
Alternative approaches to IP administration have been proposed, such as formulating cisplatin with a polymeric matrix material, for example in particle form, to provide a depot for extended release of the drug. Reported depot approaches involve drug laden polymeric particles that are administered to the desired site and release the drug over a period of time. One disadvantage of polymeric particles is that they require a significant amount of polymeric material in the formulation to reliably control the release of the cytotoxic agent. The mass of polymer significantly exceeds the mass of drug in such formulations. For example, repeated administration could result in the accrual of polymeric materials within the patient and could limit the frequency of administration possible. Another disadvantage of this approach is that the drug administration is essentially irreversible. Thus, if the dosage is administered for the entire therapy, one cannot readily, if at all, remove the drug if the therapy is not tolerated. A third disadvantage of polymeric particle administration is that release from such formulations is strongly affected by the chemistries of the drug and polymeric material. Consequently, the rate of release is limited once the materials are selected, and varying release rates is very complicated. For example, bulk polymers, such as polylactic acid, result in non-zero order releases while a constant, zero-order release rate is often preferred in drug delivery.
Liposomes have also emerged as a popular drug-carrying vehicle in recent years; however, for the same reasons as with the polymer materials, these formulations are not ideal for the treatment of ovarian cancer.
Paclitaxel is another commonly used drug in the current ovarian cancer treatment. It is dosed IV 135 mg/kg post-surgery over 24 hours or IP 60 mg/kg on Day 8. It is a hydrophobic small molecule that has a log P of about 3.5 (DrugBank, DB01229). Several patents disclose incorporating paclitaxel into degradable polymer microparticles for drug release locally. For example, U.S. Pat. No. 6,855,331 to Vook et al. discloses releasing hydrophobic drugs using the polylactic glycolic acid (PLGA) particles. However, the PLGA particles could only sustain a relatively linear release profile up to about Day 11 before a sharp drop in the release rate was observed. Those microparticles could only release for up to 25% of the paclitaxel loaded into the microparticles before the plateau.
In another example, U.S. Pat. No. 6,479,067 to Dang discloses a method of using poly(phosphoester) particles to release paclitaxel and other small molecules such as lidocaine, cisplatin, and doxorubicin. The release of cisplatin from these microparticles, however, is not well controlled, as 45% of the loaded cisplatin was released through Day 1 in one of the in vitro release experiments, and another 30% was released in the subsequent 3 days. In another in vitro release experiment with cisplatin, only 5% of cisplatin was released over 3 days, and almost no cisplatin was released over the rest of the 14 days of in vitro release. The release of paclitaxel was the most consistent among all the drugs mentioned.
The only in vivo efficacy study performed was with OVCAR-3 ovarian tumor cell line which compared microparticles containing palictaxel at a dose of 10 and 40 mg/kg to free paclitaxel of 10 and 40 mg/kg. The results showed that at the 10 mg/kg dose, there is no significant difference between the microparticle formulation and free paclitaxel (70 and 60 days respectively); at 40 mg/kg, the median survival of microparticle formulation is about 110 days, while that of free paclitaxel is about 70 days. This dose is quite high compared with conventional dosing in mice. The standard maximum dose of paclitaxel in the mouse model is 20 mg/kg. (Balthasar, et al., Cancer Chemother. Pharmacol. 68, 951-958 (2011)). However, 50 mg/kg has been used to investigate the neurophysiological and neuropathological damage in mice. The dose of 20 mg/kg is, therefore, a better comparison between the efficacy of the microparticles and free paclitaxel.
In another proposed alternative therapy, a group from University of California, San Diego recently developed a type of CD44-targeting hyaluronan-based microparticle that can encapsulate cisplatin. (De Stefano, et al., Cancer Chemother. Pharmacol. 68, 107-116 (2011)). CD44 is a surface ligand that is expressed on some types of ovarian cancer cells and hyaluronan is a natural ligand for CD44. However, these particles can only increase cisplatin uptake for CD44-positive ovarian cancer cell lines. Although these particles managed to prolong cisplatin half-life in the peritoneal cavity (when administered IP) to 124 minutes from 18 minutes in IP bolus injection, it still decreased quickly.
Accordingly, a new ovarian cancer treatment regimen that avoids the prolonged use of a catheter, eliminates or minimizes the use depot matrix materials in the drug formulation, is inexpensive, and is simple to administer would be favorable for both clinicians and patients. A significant need therefore exists for new systems and methods for local drug delivery and controlled release of drugs in the treatment of ovarian cancer. Improved systems and methods for continuous or extended intraperitoneal delivery of drug are needed.